Pharmacogenetic Impact of VKORC1 and CYP2C9 Allelic Variants on Warfarin Dose Requirements in a Hispanic Population Isolate

Abstract

Warfarin is the most prescribed oral anticoagulant worldwide. Because of the complexity of warfarin therapy, we attempted to dissect genetic from bioenvironmental factors influencing warfarin dose responses in individuals of a genetic isolate of Hispanic ancestry. A total of 191 patients with standard values of international normalized ratio were recruited. Three groups with a significantly different warfarin dose response were identified, that is, sensitive (2.28 +/- 0.50 mg/d), intermediate (4.2 +/- 0.76 mg/d), and resistant (7.40 +/- 1.54 mg/d; Tukey test, P < .001). Age had a significant inverse correlation with warfarin dose (P < .001; effective dose diminished 0.56 mg/d/decade). Required doses were higher for individuals with CYP2C9 variants containing the allele *1 compared to those individuals with variants composed of other alleles (P = .006). Similarly, individuals with VKORC1-1639GG and VKORC1-1639GA genotypes also required higher doses compared to the AA genotype (P < .001). Evaluation of potential gene-gene interactions between CYP2C9 and VKORC1 polymorphisms showed significant differences in dosing for CYP2C9 genotypes within the VKORC1-1639G/A subgroup (P = .013). A stepwise multivariate linear regression analysis showed that 38.2% of the warfarin dose response variance was accounted for by a model involving age (20.9%), VKORC1-1639G/A (11.3%), and CYP2C9*1, *2, and *3 variants (7.1%). These results corroborate previous findings on warfarin pharmacogenetics and define a contrastable gene-bioenvironment interaction model suited to be used in Hispanic populations.

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

“…La región Andina se caracteriza por el predominio de individuos caucásicos mestizos (30), que según las estimaciones corresponden a 85,9 % de los habitantes de Colombia (31). Por otra parte, a pesar de pequeñas diferencias, el porcentaje de genotipos con el polimorfismo en forma heterocigótica u homocigótica en la posición -1639 del VKORC1, fue similar al publicado en estudios llevados a cabo en población colombiana de Bogotá, Risaralda (21), y Antioquia (20). Lo mismo se observó con los polimorfismos en el gen CYP2C9.…”

Clinical applications of pharmacogenomics guided warfarin dosing

“…A multitude of retrospective [14][15][16][17][18][19][20][21][22][23] and prospective [11,[24][25][26][27][28][29][30][31][32][33][34] studies conducted since, have now clearly established the significant influence of polymorphism in CYP2C9 [9-11, 14, 15, 23, 24, 26, 28, 29, 32] and VKORC1 [9,10,23,26,28,32] genes on metabolism, and hence, the anticoagulant activity of warfarin. Thus, individuals homozygous for the CYP2C9*1 allele require a higher maintenance dose compared to the CYP2C9*2 (R 144 C) and CYP2C9*3 (I 359 L) homozygotes, respectively.…”

“…However, additional studies with larger cohorts [20,33,34] have allowed researchers to define two haplotyes composed of at least six variations across the entire coding as well as non-coding regions of the VKORC1 gene. Individuals homozygous for haplotype A are characterized by a resistant phenotype, whereas individuals homozygous for haplotype B exhibit a sensitive phenotype, the heterozygous subjects showing an intermediate response.…”

“…In recent years, advent of the genomic technologies has allowed researchers to evaluate the combined effects of genetic polymorphism in CYP2C9 as well as VKORC1 genes on sensitivity to warfarin [16,17,20,25,27,31,32,34,35]. Interestingly, a limited number of reports have also investigated potential association of polymorphism in the genes for CYP4F2 [36,37], EPHX1 [37], Apolipoprotein E [28], clotting protein FVII [22], c-glutamyl carboxylase [25], and the vitamin K epoxide reductase complex 1 like protein [19], with sensitivity to warfarin.…”

VKORC1 -1639 G>A Polymorphism in Romanian Patients With Deep Vein Thrombosis

“…Thus, the influence of the variant genotype of the VKORC1 -1693 G>A polymorphism was demonstrated on the therapeutic dose of acenocoumarol or warfarin. [14][15][16] Moreover, the involvement in the development of arterial and venous embolic events has also been studied. Studies have shown that patients with VKORC polymorphism mutant genotypes are at high risk of stroke and coronary heart disease.…”